Chimeric Antigen Receptor T-cell (CART) Therapy

Chimeric Antigen Receptor T-cell (CART) Therapy

1. Introduction
CART therapy is a revolutionary form of immunotherapy using genetically modified autologous T cells. These cells express a synthetic receptor—chimeric antigen receptor (CAR)—targeting specific tumor antigens, notably CD19 in B-cell malignancies.

2. Structure of CARs

• 1st Generation: Intracellular CD3ζ domain only.
• 2nd Generation: CD3ζ + one co-stimulatory domain (e.g., CD28 or 4-1BB).
• 3rd Generation: CD3ζ + two co-stimulatory domains.
• 4th Generation (TRUCKs): Include cytokine expression modules (e.g., IL-12).

3. CAR-T Cell Manufacturing

• Leukapheresis to collect patient’s T cells.
• Ex vivo activation and transduction with viral vectors (lentivirus or retrovirus).
• Expansion and quality control.
• Lymphodepleting chemotherapy (typically fludarabine + cyclophosphamide).
• CART cell infusion.

4. Clinical Indications

• Tisagenlecleucel (Kymriah): Pediatric ALL, DLBCL.
• Axicabtagene ciloleucel (Yescarta): LBCL, PMBCL.
• Lisocabtagene maraleucel (Breyanzi): LBCL.
• Idecabtagene vicleucel (Abecma): Multiple myeloma (BCMA-targeting).
• Expansion into solid tumors remains under investigation.

5. Mechanism of Action
CAR binds tumor antigen → T-cell activation → cytokine release → cytotoxic lysis of cancer cells. Independent of MHC, allowing broader applicability.

6. Benefits

• High response rates in refractory hematologic malignancies.
• Durable remissions in subsets.
• "Living drug" with potential for in vivo expansion and memory.

7. Toxicities and Management

• Cytokine Release Syndrome (CRS): Managed with tocilizumab and steroids.
• ICANS: Encephalopathy, seizures; managed supportively.
• B-cell aplasia: Due to CD19 targeting—requires IVIG support.
• Other risks: HLH/MAS, infections, prolonged cytopenias.

8. Challenges

• Antigen escape and tumor heterogeneity.
• Limited efficacy in solid tumors.
• High cost and logistic complexity.
• Manufacturing delays and failures.

9. Future Directions

• Dual-target CARs (e.g., CD19 + CD22).
• Allogeneic (“off-the-shelf”) CARTs.
• Combination therapies (checkpoint inhibitors, oncolytic viruses).
• Novel antigens and armored CARs for solid tumors.
• Safety switches and tunable CARs to mitigate toxicities.

10. Conclusion
CART therapy has revolutionized hematologic oncology by offering curative potential in otherwise refractory diseases. However, balancing efficacy with safety, cost, and accessibility remains crucial. Continuous innovation is essential to expand its utility, especially into solid tumor indications.